Alteration of human macrophage phenotypes by the anti-fibrotic drug nintedanib
Alteration of human macrophage phenotypes by the anti-fibrotic drug nintedanib
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DOI：
10.1016/j.intimp.2019.03.061
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发表时间：
2019-07-01
影响因子：
5.6
通讯作者：
Vernhet, Laurent
中科院分区：
文献类型：
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作者：
Bellamri, Nessrine;Morzadec, Claudie;Vernhet, Laurent
酪氨酸激酶抑制剂尼达尼布（NTD）已被批准用于治疗特发性肺纤维化（IPF）。在无细胞系统中，NTD 最近被证明可以抑制人重组集落刺激因子 1 (CSF1) 受体 (CSF1R) 的激酶活性，该受体介导肺巨噬细胞的主要功能。在本研究中，我们研究了 NTD 对 CSF1 控制的人单核细胞来源的巨噬细胞表型的影响，以鉴定其通过抑制 CSF1R 的抗炎特性。 NTD（0.01至1μM）可阻止CSF1诱导的CSF1R磷酸化和下游信号通路的激活。 NTD 与 CSF1R 抑制剂 GW2580 一样，显着降低巨噬细胞的粘附和趋化因子配体 (CCL) 2 的产生。NTD 还改变了巨噬细胞对经典 M1 和替代 M2a 巨噬细胞的极化。它减少了 M1 巨噬细胞分泌的几种促炎和/或促纤维化细胞因子（IL-1β、IL-8、IL-10 和 CXCL13），但不阻止 M1 标记物的表达。虽然 NTD (50-200 nM) 部分阻断了 M2a 标记物（CD11b、CD200R、CD206 和 CD209）的合成，但它并没有减少 M2a 促纤维化细胞因子 CCL22 和 PDGF-BB 的合成，并且在最高浓度（1 μM）使用时增加了 CCL18 的释放。 GW2580 仅部分模仿 NTD 对巨噬细胞极化的影响，表明该药物还抑制 CSF1R 之外的其他分子。总之，NTD 主要通过阻断 CSF1R 的激活来改变 CSF1 控制的人类巨噬细胞表型，从而构成 NTD 的新分子靶标，至少在体外是这样。
The tyrosine kinase inhibitor, Nintedanib (NTD), has been approved for the treatment of idiopathic pulmonary fibrosis (IPF). In cell-free systems, NTD was recently shown to inhibit kinase activity of the human recombinant colony-stimulating factor 1 (CSF1) receptor (CSF1R) which mediates major functions of pulmonary macrophages. In the present study, we have investigated the effects of NTD on the phenotype of human monocytederived macrophages controlled by CSF1 in order to identify its anti-inflammatory properties via CSF1R inhibition. NTD (0.01 to 1 mu M) prevented the CSF1-induced phosphorylation of CSF1R and activation of the downstream signaling pathways. NTD, like the CSF1R inhibitor GW2580, significantly decreased the adhesion of macrophages and production of the chemokine ligand (CCL) 2. NTD also altered the polarization of macrophages to classical M1 and alternative M2a macrophages. It reduced the secretion of several pro-inflammatory and/or pro-fibrotic cytokines (IL-1 beta, IL-8, IL-10 and CXCL13) by M1 macrophages but did not prevent the expression of M1 markers. While NTD (50-200 nM) partially blocked the synthesis of M2a markers (CD11b, CD200R, CD206, and CD209), it did not reduce synthesis of the M2a pro-fibrotic cytokines CCL22 and PDGF-BB, and increased CCL18 release when used at its highest concentration (1 mu M). The effects of NTD on macrophage polarization only was partially mimicked by GW2580, suggesting that the drug inhibits other molecules in addition to CSF1R. In conclusion, NTD alters the CSF1-controlled phenotype of human macrophages mainly by blocking the activation of CSF1R that thus constitutes a new molecular target of NTD, at least in vitro.